ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4703A>G (p.His1568Arg) (rs368830730)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131606 SCV000186622 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing The p.H1568R variant (also known as c.4703A>G), located in coding exon 30 of the ATM gene, results from an A to G substitution at nucleotide position 4703. The histidine at codon 1568 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000167871 SCV000218517 uncertain significance Ataxia-telangiectasia syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1568 of the ATM protein (p.His1568Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs368830730, ExAC 0.01%). This variant has been observed in an individual with telomere shortening and related conditions and in several individuals that underwent multi-gene hereditary cancer testing (PMID: 30995915, 31159747). ClinVar contains an entry for this variant (Variation ID: 142472). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480209 SCV000566386 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.4703A>G at the cDNA level, p.His1568Arg (H1568R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant was observed in at least one individual undergoing multi-gene hereditary cancer panel testing (Mu 2016). ATM His1568Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM His1568Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000131606 SCV000821855 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131606 SCV000902861 likely benign Hereditary cancer-predisposing syndrome 2017-01-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000167871 SCV001462337 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355688 SCV001550643 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.His1568Arg variant was identified in 1 of 40,106 proband chromosomes (frequency: 0.00003) from individuals with unspecified hereditary cancer and was present in 1 of 24,980 control chromosomes (frequency: 0.00004) from healthy individuals (Momozawa 2018, Mu 2016). The variant was identified in dbSNP (rs368830730) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and GeneKor; and as likely benign by Color) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 10 of 245,814 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 10 of 111,368 chromosomes (freq: 0.00009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His1568 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.